The study aims at assessing the efficacy and the safety of hydrocortisone combined with fludrocortisone compared to placebo in ICU adults with critical illness related corticosteroid insufficiency.

The hypothalamic-pituitary-adrenal axis together with the noradrenergic/vasopressinergic system are the main systems of host response to stress. In 2008 the scientific community described a syndrome called critical illness related corticosteroids insufficiency (CIRCI) in which body homeostasis is lost owing to insufficient cortisol production or bioactivity in tissues. Recent updates of international guidelines have spelled out the pathophysiology, diagnosis and management of CIRCI. The prevalence of CIRCI varies according to case mix and severity of illness. The combination of hydrocortisone and fludrocortisone improved outcomes in septic shock, a condition often complicated with CIRCI. However, there is insufficient evidence on the efficacy of corticosteroids in patients with CIRCI and without septic shock. The hypothesis of the study is that the hydrocortisone-fludrocortisone association will improve ventilation and vasopressor free survival in ICU patients with Critical illness related Corticosteroid Insufficiency.

Patients with a SOFA score ≥ 4 will be screened for CIRCI. Patients suffering from CIRCI will be randomized to receive hydrocortisone and fludrocortisone or their placebo. Patients without CIRCI will receive standard of care and will be followed up during 90 days (cohort-observational study).

Inclusion Criteria:

• Adult (≥ 18 years);
• Hospitalized in an intensive care unit;
• SOFA score ≥ 4, for at least 6 consecutive hours;
• Informed written consent from patient or from legally authorized next of kin, or emergency deferred consent;
• Affiliation to a social security system or to a universal health coverage (Couverture Maladie Universelle, CMU).

Exclusion Criteria:

• Any suspected or proven acute adrenal insufficiency (As defined in international guidelines; basal cortisol < 5 μg/dL or peak (60) cortisol <18 μg/dL)
• Expected death or withdrawal of life-sustaining treatments within 48 hours
• Known chronic adrenal insufficiency
• Concomitant treatment that inhibits cortisol production
• Septic shock (Singer Jama 2016)
• Active tuberculosis or fungal infection
• Active viral hepatitis or active infection with herpes viruses
• Hypersensitivity or contraindication to hydrocortisone, fludrocortisone or Synacthène® or any of their excipients ( SmPC)
• Patient needing either anti-inflammatory corticosteroids or substitutive hydrocortisone for any reason (Such as those suffering from COVID-19 pneumonia requiring oxygen therapy).
• Current treatment by more than 15 mg/d of prednisone (or equivalent) for more than 30 days
• Diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome
• Pregnant or breastfeeding woman
• Moribund patient
• Previously enrolled in this study
• Participation to another interventional study that focuses on CIRCI and/or corticoid drugs and/or that addresses a similar primary endpoint as Hornbill ( ventilator- and vasopressor-free survival )
• Patient under guardianship or tutorship

Note: Included patients for whom acute adrenal insufficiency would be detected in the Synacthen ® test performed as part of the research for the diagnosis of CIRCI will not be randomized since they should be treated by corticosteroids.